Huang, H.; Zhu, X.; Chen, X.; Chen, F.; Cheng, S.; Ding, S.; Xiao, Y.; Xie, X.; Cheng, C.; Yang, R.; Chen, J.; Liu, J.; Yang, X.; Yang, C.; Shi, B.; Shao, D.; Zhao, L.; Leong, K. W.

Periodontitis-associated systemic inflammation makes it a great challenge to explore therapeutic options applicable to periodontitis and atherosclerotic comorbidities. Here, we identify the crucial role of cell-free DNA (cfDNA) that underlies these comorbidities. Hypothesizing cfDNA as a therapeutic target, we engineer polyamidoamine dendrimer-functionalized nanomaterials to modulate such local-systemic inflammatory crosstalk. Periodontium-originated DNA can be systemically captured by cationic nanomaterials, and capturing cfDNA, whether locally or systemically, alleviates both periodontitis and atherosclerosis prior to severe atherosclerotic development in vivo. The transcriptomic and single-cell RNA sequencing analyses together reveal that cfDNA-capturing nanomaterials regulate inflammatory foam cell transformation in macrophages by modulating the expression of lipid-related foamy markers Spp1 and Fabp4. This study provides a proof of concept for cfDNA-driven periodontitis-atherosclerosis crosstalk, and offers a cfDNA-capturing nanoplatform for therapeutic intervention targeting periodontitis and atherosclerotic comorbidities in a holistic fashion.